A systematic review of interventions to provide genetics education for primary care.

BACKGROUND: At least 10 % of patients seen in primary care are said to have a condition in which genetics has an influence. However, patients at risk of genetic disease may not be recognised, while those who seek advice may not be referred or managed appropriately. Primary care practitioners lack knowledge of genetics and genetic testing relevant for daily practice and feel inadequate to deliver genetic services. The aim of this systematic review was to evaluate genetics educational interventions in the context of primary care. METHODS: Following the process for systematic reviews developed by the Centre for Reviews and Dissemination, we conducted a search of five relevant electronic databases. Primary research papers were eligible for inclusion if they included data on outcomes of interventions regarding genetics education for primary care practitioners. The results from each paper were coded and grouped under themes. RESULTS: Eleven studies were included in the review. The five major themes identified inductively (post hoc) were: prior experience, changes in confidence, changes in knowledge, changes in practice, satisfaction and feedback. In five of the studies, knowledge of practitioners was improved following the educational programmes, but this tended to be in specific topic areas, while practitioner confidence improved in six studies. However, there was little apparent change to practice. CONCLUSIONS: There are insufficient studies of relevant quality to inform educational interventions in genetics for primary care practitioners. Educational initiatives should be assessed using changes in practice, as well as in confidence and knowledge, to determine if they are effective in causing significant changes in practice in genetic risk assessment and appropriate management of patients.

Effectiveness of oncogenetics training on general practitioners' consultation skills: a randomized controlled trial.

PURPOSE: General practitioners are increasingly called upon to deliver genetic services and could play a key role in translating potentially life-saving advancements in oncogenetic technologies to patient care. If general practitioners are to make an effective contribution in this area, their genetics competencies need to be upgraded. The aim of this study was to investigate whether oncogenetics training for general practitioners improves their genetic consultation skills. METHODS: In this pragmatic, blinded, randomized controlled trial, the intervention consisted of a 4-h training (December 2011 and April 2012), covering oncogenetic consultation skills (family history, familial risk assessment, and efficient referral), attitude (medical ethical issues), and clinical knowledge required in primary-care consultations. Outcomes were measured using observation checklists by unannounced standardized patients and self-reported questionnaires. RESULTS: Of 88 randomized general practitioners who initially agreed to participate, 56 completed all measurements. Key consultation skills significantly and substantially improved; regression coefficients after intervention were equivalent to 0.34 and 0.28 at 3-month follow-up, indicating a moderate effect size. Satisfaction and perceived applicability of newly learned skills were highly scored. CONCLUSION: The general practitioner-specific training proved to be a feasible, satisfactory, and clinically applicable method to improve oncogenetics consultation skills and could be used as an educational framework to inform future training activities with the ultimate aim of improving medical care.

Pharmacogenetic educational needs and the role of pharmacogenetics in primary care: a focus group study with multiple perspectives.

Background: Pharmacogenomics (PGx) is a well-established concept of how genes impact medication response, with many studies demonstrating reductions in medication side effects, improved efficacy and cost effectiveness. Despite these benefits, implementation of PGx in daily practice remains limited. Studies on the implementation of PGx in clinical practice have previously found that inadequate knowledge is one of the main barriers. Details regarding specifically which educational needs exist among family medicine clinicians requires further study. Objective: The aim of this study was to identify both the perceived role that pharmacogenomics (PGx) could play in primary care practice, the knowledge gaps that family medicine clinicians experience, and the skills they require to use PGx in their daily practice. Methods: To achieve this aim, the attitudes, knowledge, barriers, skills needed, and preferred educational program were explored in a family medicine clinician focus group study via a semi-structured interview and knowledge quiz. Second, multidisciplinary focus groups provided information on the level of knowledge and necessary skills to use PGx in patient care. After gathering key recorded information from both focus groups, the perceived role pharmacogenomics could possibly play in primary care, the predominant knowledge gaps, and the most appropriate educational program was determined by qualitative analysis. Results: Four themes emerged regarding the PGx educational needs and the role of PGx in family medicine: 1) need for PGx competences, 2) insight into the roles and responsibilities of PGx services, 3) optimization of PGx workflow through artificial intelligence integrated in the electronic health record, and 4) the ethical dilemmas and psychological effects related to PGx. These themes reflect a shift in the role of PGx in family medicine with implications for education. Conclusion: The results obtained from this study will help improve the implementation of PGx in daily practice, and consequently, may result in increased utilization of PGx, thereby resulting in improved medication efficacy and reduced side effects.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.

Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP2C19 and non-SSRI/non-TCA antidepressants.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin "essential" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine "beneficial", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

Hemoglobinopathy screening in primary care in the Netherlands: exploring the problems and needs of patients and general practitioners.

The prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Hemoglobinopathies are severe hereditary diseases. An informed reproductive choice by at-risk couples, such as pre-implantation diagnosis or termination of affected pregnancies, can be made if carriers are detected prior to conception. Using a qualitative design, the needs and wishes of patients, carriers and general practitioners were evaluated regarding carrier detection of hemoglobinopathies in primary care practice. 30 semi-structured interviews were established with 10 general practitioners, 10 patients and 10 carriers. The interviews were audio-recorded, transcribed verbatim and analysed using content analysis to identify recurring themes. Three themes were generated regarding carrier detection of hemoglobinopathies: (1) a need for more information about hemoglobinopathy, (2) a need for indications when to refer for analysis (carrier diagnostics) and (3) insight concerning organization and roles in care for hemoglobinopathy carriers and patients. These themes reflected a need to increase awareness of hemoglobinopathy, improve competences among general practitioners through better education and improvement of communication with patients and their unidentified family members. This study shows the scope of the problem and the critical need for action to improve informed reproductive decision making for the at-risk population.

Vincristine-Induced Acrocyanosis and Erythema Pernio.

INTRODUCTION: Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy. CASE DESCRIPTION: A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient's oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient's symptoms and the appearance of his feet had markedly improved. DISCUSSION: Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient's history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Personal Genomes in Practice: Exploring Citizen and Healthcare Professionals' Perspectives on Personalized Genomic Medicine and Personal Health Data Spaces Using a Mixed-Methods Design.

Ongoing health challenges, such as the increased global burden of chronic disease, are increasingly answered by calls for personalized approaches to healthcare. Genomic medicine, a vital component of these personalization strategies, is applied in risk assessment, prevention, prognostication, and therapeutic targeting. However, several practical, ethical, and technological challenges remain. Across Europe, Personal Health Data Space (PHDS) projects are under development aiming to establish patient-centered, interoperable data ecosystems balancing data access, control, and use for individual citizens to complement the research and commercial focus of the European Health Data Space provisions. The current study explores healthcare users' and health care professionals' perspectives on personalized genomic medicine and PHDS solutions, in casu the Personal Genetic Locker (PGL). A mixed-methods design was used, including surveys, interviews, and focus groups. Several meta-themes were generated from the data: (i) participants were interested in genomic information; (ii) participants valued data control, robust infrastructure, and sharing data with non-commercial stakeholders; (iii) autonomy was a central concern for all participants; (iv) institutional and interpersonal trust were highly significant for genomic medicine; and (v) participants encouraged the implementation of PHDSs since PHDSs were thought to promote the use of genomic data and enhance patients' control over their data. To conclude, we formulated several facilitators to implement genomic medicine in healthcare based on the perspectives of a diverse set of stakeholders.

Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction of CYP2D6 and COMT with atomoxetine and methylphenidate.

Pharmacogenetics (PGx) studies the effect of heritable genetic variation on drug response. Clinical adoption of PGx has remained limited, despite progress in the field. To promote implementation, the Dutch Pharmacogenetics Working Group (DPWG) develops evidence-based guidelines on how to optimize pharmacotherapy based on PGx test results. This guideline describes optimization of atomoxetine therapy based on genetic variation in the CYP2D6 gene. The CYP2D6 enzyme is involved in conversion of atomoxetine into the metabolite 4-hydroxyatomoxetine. With decreasing CYP2D6 enzyme activity, the exposure to atomoxetine and the risk of atomoxetine induced side effects increases. So, for patients with genetically absent CYP2D6 enzyme activity (CYP2D6 poor metabolisers), the DPWG recommends to start with the normal initial dose, bearing in mind that increasing this dose probably will not be required. In case of side effects and/or a late response, the DPWG recommends to reduce the dose and check for sustained effectiveness for both poor metabolisers and patients with genetically reduced CYP2D6 enzyme activity (CYP2D6 intermediate metabolisers). Extra vigilance for ineffectiveness is required in patients with genetically increased CYP2D6 enzyme activity (CYP2D6 ultra-rapid metabolisers). No interaction was found between the CYP2D6 and COMT genes and methylphenidate. In addition, no interaction was found between CYP2D6 and clonidine, confirming the suitability of clonidine as a possible alternative for atomoxetine in variant CYP2D6 metabolisers. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for atomoxetine. CYP2D6 testing prior to treatment can be considered on an individual patient basis.

Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.

Prioritization of future genetics education for general practitioners: a Delphi study.

PURPOSE: General practitioners (GPs) are increasingly expected to deliver genetics services in daily patient care. Education in primary care genetics is considered suboptimal and in urgent need of revision and innovation. The aim of this study was to prioritize topics for genetics education for general practice. METHODS: A Delphi consensus procedure consisting of three rounds was conducted. A purposively selected heterogeneous panel (n = 18) of experts, comprising six practicing GPs who were also engaged in research, five GP trainers, four clinical genetics professionals, and three representatives of patient organizations, participated. Educational needs regarding genetics in general practice in terms of knowledge, skills, and attitudes were rated and ranked in a top-10 list. RESULTS: The entire panel completed all three rounds. Kendall's coefficient of concordance indicated significant agreement regarding the top 10 genetic education needs (P < 0.001). "Recognizing signals that are potentially indicative of a hereditary component of a disease" was rated highest, followed by "Evaluating indications for referral to a clinical genetics centre" and "Knowledge of the possibilities and limitations of genetic tests." CONCLUSIONS: The priorities resulting from this study can inform the development of educational modules, including input for case-based education, to improve GP performance in genetic patient care.

FHH Quick App Review: How Can a Quality Review Process Assist Primary Care Providers in Choosing a Family Health History App for Patient Care?

Family health history (FHH) is a data type serving risk assessment, diagnosis, research, and preventive health. Despite technological leaps in genomic variant detection, FHH remains the most accessible, least expensive, and most practical assessment tool for assessing risks attributable to genetic inheritance. The purpose of this manuscript is to outline a process to assist primary care professionals in choosing FHH digital tools for patient care based on the new ISO/TS 82304-2 Technical Specification (TS), which is a recently developed method to determine eHealth app quality. With a focus on eHealth in primary care, we applied the quality label concept to FHH, and how a primary care physician can quickly review the quality and reliability of an FHH app. Based on our review of the ISO TS's 81 questions, we compiled a list of 25 questions that are recommended to be more succinct as an initial review. We call this process the FHH Quick App Review. Our 'informative-only' 25 questions do not produce a quality score, but a guide to complete an initial review of FHH apps. Most of the questions are straight from the ISO TS, some are modified or de novo. We believe the 25 questions are not only relevant to FHH app reviews but could also serve to aid app development and clinical implementation.

Hemoglobinopathy prevention in primary care: a reflection of underdetection and difficulties with accessibility of medical care, a quantitative study.

As in most Northern European countries, the prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Although hemoglobinopathies are severe chronic diseases with few treatment options, timely detection of carriers allows at-risk couples to make informed reproductive choices such as pre-implantation diagnosis, prenatal diagnosis or termination of affected pregnancies. Using a quantitative design, we evaluated the prevalence of hemoglobinopathies in The Hague region, The Netherlands. Patient and carrier registries from hospital, laboratory and general practitioners allowed this quantitative analysis. The highest prevalence of hemoglobinopathies was seen in immigrant neighborhoods, and a large gap was noted between estimated carrier prevalence and the actual registration of carriers in electronic patient records. Carrier prevalence was estimated to be 13,704; however, the ELAN database contains only 1542 cases with ICPC codes for sickle cell disease or thalassemia. Although more research is needed to define the requirements of the healthcare system to address this challenge, this study clearly shows the gap between estimated carrier prevalence and registration and thereby the pressing need for action.

[Oncogenetics]. / Oncogenetica.

Determining whether a hereditary cancer predisposition is present, is important for both the cancer patient and his family. It is relevant for surveillance and prevention or early detection of new tumours, treatment options and issues surrounding the desire to have children. For this reason, it must be ensured that for every patient with cancer (now or in the past) referral for genetic testing is considered. In this article we indicate how to take a family history and where to find and how to apply referral criteria if such a question arises in clinical practice. The consequences of a genetic diagnosis are illustrated by a breast cancer case.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone).

The current Dutch Pharmacogenetics Working Group (DPWG) guideline, describes the gene-drug interaction between CYP2D6 and the opioids codeine, tramadol and oxycodone. CYP2D6 genotype is translated into normal metaboliser (NM), intermediate metaboliser (IM), poor metaboliser (PM) or ultra-rapid metaboliser (UM). Codeine is contraindicated in UM adults if doses >20 mg every 6 h (q6h), in children ≥12 years if doses >10 mg q6h, or with additional risk factors. In PMs, an alternative analgesic should be given which is not or to a lesser extent metabolised by CYP2D6 (not tramadol). In IMs with insufficient analgesia, a higher dose or alternative analgesic should be given. For tramadol, the recommendations for IMs and PMs are the same as the recommendation for codeine and IMs. UMs should receive an alternative drug not or to a lesser extent metabolised by CYP2D6 or the dose should be decreased to 40% of the commonly prescribed dose. Due to the absence of effect on clinical outcomes of oxycodone in PMs, IMs and UMs no action is required. DPWG classifies CYP2D6 genotyping for codeine "beneficial" and recommends testing prior to, or shortly after initiation of treatment in case of higher doses or additional risk factors. CYP2D6 genotyping is classified as "potentially beneficial" for tramadol and can be considered on an individual patient basis.

Dutch pharmacogenetics working group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.